Depressive illness, which is a major source of human morbidity with enormous economic and social impact, is characterized by dysfunction of limbic circuitry, but the nature of circuitry defects that underlie this and whether they have their basis in developmentally disturbed connectivity are unknown. The overall aim of this research proposal is to identify, in humans, those genes that are specific to two limbic circuits defined by projections of the principal anterior nucleus of the thalamus to posterior cingulate cortex (Brodmann's area 23) and of the mediodorsal nucleus of the thalamus to anterior cingulate cortex (Brodmann's area 24) in brains from patients who had suffered from major depressive illness and bipolar disorder, compared with brains of matched controls and schizophrenics. We will use Affymetrix GeneChip arrays for global gene profiling and a series of higher resolution techniques for locating the cellular expression of known and novel genes that are either specific to or show different patterns of expression between the cognate pairs of cortical areas and thalamic nuclei. These studies are expected to shed light on the factors that determine the interconnectedness of specific areas of the cerebral cortex with specific nuclei of the thalamus and how these factors are disturbed in clinical conditions characterized by altered function of the cortical targets of specific thalamic nuclei. Together with additional data on mRNA levels, mutant phenotypes, protein localization, protein levels and protein interactions, the information should help us gain a better understanding of these biological systems, develop improved diagnostic tests, identify new therapeutic targets, and potentially lead to novel treatment strategies for bipolar and major depressive disorders.